Angiogenesis is an essential process not only in normal development, but in pathological conditions such as tumor growth and metastasis. New and improved methods for preventing angiogenesis require an understanding of the mechanisms that regulate angiogenesis. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR-lIFlt-l and VEGFR-2/Flk-1/KDR) are considered to be primary regulators of tumor-induced angiogenesis. Activation of VEGFR-2 stimulates angiogenesis, while VEGFR- 1 activation appears to play a dual function by either stimulating angiogenesis or suppressing angiogenesis. Therefore, understanding the molecular mechanisms underlying these strikingly different effects is essential for development of targeted therapeutic interventions aimed at angiogenesis suppression. The overall goal of this proposal is to investigate the mechanism by which VEGFRS are activated and to exploit these differences to suppress angiogenesis. This proposal focuses on the mechanism by which ligand binding results in the activation of VEGF receptors, a fundamental issue in signal transduction and angiogenesis. Once we determine the mechanism by which VEGF receptors are engaged it will be possible to attenuate the angiogenic signal transduction relay by developing targeted therapeutic interventions aimed at angiogenesis suppression